Influenza A viruses pose a major public health problem, causing seasonal epidemics and occasional—but devastating—global pandemics (Cunha B A (2004) Influenza: historical aspects of epidemics and pandemics. Infectious disease clinics of North America 18(1):141-155) which negatively impact the global economy. Until recently, influenza pandemics were thought to always be associated with the introduction of new HA subtypes into the human population. Indeed, two of the twentieth century pandemics—the 1957-58 H2N2 Asian Flu and the 1967-68 H3N2 Hong Kong Flu—involved precisely this scenario (Scholtissek C, Rohde W, Von Hoyningen V, & Rott R (1978) On the origin of the human influenza virus subtypes H2N2 and H3N2. (Translated from eng) Virology 87(1):13-20 and Kawaoka Y, Krauss S, & Webster R G (1989) Avian-to-human transmission of the PB1 gene of influenza A viruses in the 1957 and 1968 pandemics. (Translated from eng) J Virol 63(11):4603-4608).
However, more recent experiences have revealed that historical strains can sometimes re-emerge in the human population, with potentially devastating effects. This phenomenon results from influenza's mode of antigenic variation, and the interplay between the different host systems that impact it.
The surface glycoprotein HA of the influenza A virus is the main target of the immune system and mutations on the globular head region (residues 50-230 of HA1, H3 HA numbering used) of this protein determine antigenic novelty, species adaptation, and transmission (Webster R G, Bean W J, Gorman O T, Chambers T M, & Kawaoka Y (1992) Evolution and ecology of influenza A viruses. (Translated from eng) Microbiol Rev 56(1):152-179).
Birds are natural reservoirs for influenza A viruses and avian-adapted viruses regularly cross over to humans, either directly (through direct contact) or through an intermediate swine species. Influenza A virus strains rapidly evolve (through antigenic drift) in humans as a consequence of both the complex response of human immune system and rapid geographical movement of human population. In contrast to their rapid antigenic evolution in human hosts, the antigenic evolution of influenza A strains in avian and swine hosts occurs at a much slower rate. As a consequence of these factors, the human immunity to past pandemic strains fades over time, thus enabling antigenically “intact” viruses in avian and swine species to reemerge and begin a new infection cycle in humans.
For example, although H2N2 subtype does not currently circulate in the human population, virus strains with HAs that are antigenically similar to the 1957-58 pandemic H2N2 virus continue to circulate in avian species. Among the subtypes that continue to circulate in humans (H1N1 and H3N2), the 2009 H1N1 outbreak offers a practical example of how HA from a swine strain that is antigenically similar to 1918 pandemic H1N1 HA can be reintroduced into the human population. The question remains of whether this trend is observed in H3N2, given that there has been a high rate of antigenic drift in human H3 subtype since the emergence of 1968 pandemic H3N2.
The H3N2 pandemic began in 1968 and was caused by a human-adapted H2N2 virus that obtained avian H3 and PB1 genes through reassortment. The HAs of both 1957 and 1968 pandemic strains are of avian origin. Unlike H2N2, the H3N2 subtype is still in circulation, however the high rate of antigenic drift of human H3 coupled with the long interval since the previous pandemic may mean that the human herd would have ‘forgotten’ the antigenic structure of the 1968 pandemic strain and therefore the reemergence of a similar strain circulating in the avian or swine reservoir could have potentially damaging consequences. Identifying such strains is of paramount value for pandemic surveillance and preparedness; treating them is critical for survival.